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Protocol development in integrative medicine is not typically a simple process. Individuals require individualized care, and what works for one patient may not work for another.

To establish these protocols, we first developed a Rating Scale that could be used to discern the rigor of evidence supporting a specific nutrient’s therapeutic effect.

The following protocols were developed using only A through C-quality evidence.

Class
Qualifying studies
Minimum requirements
A
Systematic review or meta-analysis of human trials
 
B
RDBPC human trials
2+ studies and/or 1 study with 50 + subjects
C
RDBPC human trials
1 study

Optimal ovarian wellness may include management of reproductive hormonal or endocrine disorders such as polycystic ovarian syndrome (PCOS), which is reported to affect approximately 6% to 10% of women. (3) PCOS affects multiple systems, causing problems with reproductive, metabolic, and psychological factors. Reproductive issues such as infertility, adverse pregnancy outcomes, and endometrial cancer are all possibilities. Metabolic factors and possible comorbidities include obesity, type 2 diabetes mellitus, insulin resistance, and metabolic syndrome. (11

Due to the system-wide nature of PCOS, the intervention targets need to have a similar approach. Common therapies such as pharmaceutical hormone regulation are used in many PCOS patients, as well as metformin for the metabolic aspects. 

The protocol presented below aims to address different aspects of the root causes for women suffering from PCOS.

1-2 g inositol (myo-inositol and d-chiro-inositol), minimum 3 months (6)(19)(21)

  • In a meta-analysis, myoinositol was found to improve the homeostatic model assessment (HOMA), increase total testosterone and estradiol, and alleviate insulin resistance (27)
  • Women with PCOS given 1200 mg of d-chiro-inositol twice daily experienced improved insulin sensitivity as measured by oral glucose tolerance test (4)
  • When comparing 6 months of supplementation with 4g of myo-inositol(MI) or 1g of d-chiro-inositol(DCI), both therapies improved ovarian and metabolic functions; however, myoinositol was superior for metabolic function and di-chiro-inositol was superior in decreasing hyperandrogenism (21)
  • Patients given 2g of inositol twice per day for 3 months at a variety of myo-inositol (MI) to d-chiro-inositol (DCI) ratios, it was found that the 40:1 MI/DCI ratio was ideal for restoring and normalizing ovulation in PCOS patients (19)
  • Women with PCOS undergoing IVF-ET demonstrated higher pregnancy rates and improved quality of oocytes and embryos when treated with the combination therapy of 1.1 g of MI with 27.6 mg of DCI compared to 500 mg of DCI only (6)
  • When comparing MI with DCI versus MI alone for 6 months of treatment, both groups had pronounced improvements; however combined MI and DCI was more effective after 3 months of treatment (20)
Inositol in the Fullscript catalog

Omega-3 with Vitamin E 

1000 mg of omega-3 with 400 IU vitamin E (8)(22)

  • Insulin resistance decreased as shown by improvements in homeostasis model of insulin resistance (HOMA), decreased insulin, and increased quantitative insulin sensitivity check index; additionally, total and free testosterone improved compared to placebo when given 1000 mg omega-3 fatty acids from flaxseed oil containing 400 mg α-Linolenic acid and 400 IU vitamin E supplements (8)
  • Obese and/or overweight women with PCOS demonstrated increased total antioxidant capacity, catalase activity, and glutathione levels as well as decreased malondialdehyde concentration compared to placebo when given 2 g of omega-3 with 400 IU of vitamin E (23)
  • Gene expression, lipid profile, and oxidative stress all improved as shown by downregulated expressed levels of Lp(a) mRNA and Ox-LDL mRNA in peripheral blood mononuclear cells, decreased serum triglycerides, VLDL, total, LDL, and total/HDL, and increased plasma total antioxidant capacity, decreased malondialdehyde levels compared to placebo when supplemented for 12 weeks (22)
  • PCOS patients improved gene expression as shown by upregulated peroxisome proliferator-activated receptor gamma (PPAR-γ) and mRNA in peripheral blood mononuclear cells and downregulated expressed levels of oxidized low-density lipoprotein receptor (LDLR) mRNA in peripheral blood mononuclear cells compared to placebo when given 1000 mg omega-3 fatty acids from flaxseed oil containing 400 mg α-linolenic acid  for 12 weeks (18)
  • Systematic review and meta-analysis of 9 trials found omega-3 fatty acids may improve insulin resistance in patients with PCOS (26)  
Omega-3 with Vitamin E in the Fullscript catalog

Vitamin D

50,000 IU once per week, or once every other week, for a minimum of 8 weeks (7)(24) or 1000 IU per day for a minimum of 12 weeks (14

  • When given 50,000 IU once per week, insulin sensitivity improved in IVF candidates with PCOS as demonstrated by decreased insulin and HOMA for insulin resistance (HOMA-IR) compared to placebo; additionally, a decrease in serum anti-Müllerian hormone (AMH) was observed (7)
  • In a systematic review of 11 studies, it was found that continuous supplementation of vitamin D up to 4000 IU per day was associated with improved insulin sensitivity and HOMA-IR (16)
  • When comparing vitamin D, placebo, or metformin in the treatment of PCOS, a systematic review and meta-analysis of 9 studies found both metformin and vitamin D individually improved follicular development, while metformin with vitamin D had more pronounced improvements on menstrual cycle regulation (9)
  • PCOS patients deficient in vitamin D (as defined by a plasma 25-OH vitamin D <20 ng/mL) had decreased fasting plasma glucose and increased HOMA for B-cell function, adiponectin, and serum vitamin D when supplemented 50,000 IU once per week for 8 weeks compared to placebo (24)
  • When comparing doses of 4,000 IU per day, 1000 IU per day, or placebo, high dose vitamin D had the most pronounced decreases in total testosterone, free androgen index (FAI), hirsutism, and high-sensitivity CRP, and elevations of sex hormone-binding globulin (SHBG) and total antioxidant capacity in insulin-resistant PCOS patients (14)
Vitamin D in the Fullscript catalog

Berberine

500 mg per day, for a minimum of 3 months (5)

  • Infertile women with PCOS undergoing IVF experienced decreased total testosterone, free androgen index, fasting glucose, fasting insulin and HOMA-IR, BMI, lipid parameters and total FSH requirement, and an increase in live birth rate and SHBG when given berberine or metformin in comparison to placebo; additionally fewer gastrointestinal adverse events were observed in the berberine group and was superior for live birth weight, lipid parameters, and total FSH compared to metformin (1
  • Berberine with cyproterone acetate lead to decreases in the waist circumference and waist-to-hip ratio, total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol, as well as increase in high-density lipoprotein cholesterol (HDLC) and sex hormone-binding globulin in women with PCOS and insulin resistance compared to metformin and cyproterone acetate group and placebo group (25)  
  • In a meta-analysis and systematic review of 9 randomized controlled trials, berberine was found to be comparable to metformin as demonstrated by no significant differences found between them in alleviating insulin resistance, improving glycolipid metabolism or reproductive endocrine condition (17)
  • Lipid metabolism improved as shown by improved BMI, HOMA index, FPG, LDL-C, HDL-C, TG, hsCRP in women with and without PCOS who had oral contraceptive induced hypercholesterolemia (5
Berberine in the Fullscript catalog

Chromium picolinate

200 µg, per day, minimum 8 weeks (12)(13)

  • Improved glycemic control as demonstrated by  significant reductions in fasting plasma glucose, insulin levels, homeostatic model of assessment for insulin resistance, and a significant increase in quantitative insulin sensitivity check index; improved cardio-metabolic risk demonstrated by decreased serum triglycerides, VLDL and total cholesterol concentrations (15)
  • A systematic review and meta-analysis of 7 randomized controlled trials found overall reductions in BMI, fasting insulin, and free testosterone concentration (10
  • When given 1000 μg CrP for 6 months, PCOS patients experienced decreased BMI and FSI, as well as increased chance of ovulation and regular menstruation after five months of treatment compared to placebo (2)
  • Improved metabolic profile as demonstrated by decreased serum insulin levels, HOMA-IR, HOMA-B (beta cell function) and increase in quantitative insulin sensitivity check index (QUICKI) score compared to placebo (12)
  • Improved pregnancy rate by 16.7% compared to 3.3% in placebo, decreased prevalence of acne by 20.0 compared to 3.3% in placebo; additionally, chromium improved oxidative stress as shown by increased total antioxidant capacity and decreased hirsutism, serum hsCRP, plasma MDA (malondialdehyde) (13)
Chromium picolinate in the Fullscript catalog

Disclaimer

The Fullscript Integrative Medical Advisory team has developed or collected these protocols from practitioners and supplier partners to help health care practitioners make decisions when building treatment plans. By adding this protocol to your Fullscript template library, you understand and accept that the recommendations in the protocol are for initial guidance and may not be appropriate for every patient.

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References
  1. An, Y., Sun, Z., Zhang, Y., Liu, B., Guan, Y., & Lu, M. (2014). The use of berberine for women with polycystic ovary syndrome undergoing IVF treatment. Clinical Endocrinology, 80(3), 425–431. https://pubmed.ncbi.nlm.nih.gov/23869585/ (C)
  2. Ashoush, S., Abou-Gamrah, A., Bayoumy, H., & Othman, N. (2016). Chromium picolinate reduces insulin resistance in polycystic ovary syndrome: Randomized controlled trial. The Journal of Obstetrics and Gynaecology Research, 42(3), 279–285. https://pubmed.ncbi.nlm.nih.gov/26663540/ (B)
  3. Bozdag, G., Mumusoglu, S., Zengin, D., Karabulut, E., & Yildiz, B. O. (2016). The prevalence and phenotypic features of polycystic ovary syndrome: a systematic review and meta-analysis. Human Reproduction, 31(12), 2841–2855. https://pubmed.ncbi.nlm.nih.gov/27664216/ (A)
  4. Cheang, K. I., Baillargeon, J.-P., Essah, P. A., Ostlund, R. E., Jr, Apridonize, T., Islam, L., & Nestler, J. E. (2008). Insulin-stimulated release of D-chiro-inositol-containing inositolphosphoglycan mediator correlates with insulin sensitivity in women with polycystic ovary syndrome. Metabolism: Clinical and Experimental, 57(10), 1390–1397. https://pubmed.ncbi.nlm.nih.gov/18803944/ (C)
  5. Cicero, A. F. G., Reggi, A., Parini, A., Morbini, M., Rosticci, M., Grandi, E., & Borghi, C. (2014). Berberine and monacolin effects on the cardiovascular risk profile of women with oestroprogestin-induced hypercholesterolemia. High Blood Pressure & Cardiovascular Prevention: The Official Journal of the Italian Society of Hypertension, 21(3), 221–226. https://pubmed.ncbi.nlm.nih.gov/24728953/ (C) 
  6. Colazingari, S., Treglia, M., Najjar, R., & Bevilacqua, A. (2013). The combined therapy myo-inositol plus D-chiro-inositol, rather than D-chiro-inositol, is able to improve IVF outcomes: results from a randomized controlled trial. Archives of Gynecology and Obstetrics, 288(6), 1405–1411. https://pubmed.ncbi.nlm.nih.gov/23708322/ (C)
  7. Dastorani, M., Aghadavod, E., Mirhosseini, N., Foroozanfard, F., Zadeh Modarres, S., Amiri Siavashani, M., & Asemi, Z. (2018). The effects of vitamin D supplementation on metabolic profiles and gene expression of insulin and lipid metabolism in infertile polycystic ovary syndrome candidates for in vitro fertilization. Reproductive Biology and Endocrinology: RB&E, 16(1), 94. https://pubmed.ncbi.nlm.nih.gov/30286768/ (C)
  8. Ebrahimi, F. A., Samimi, M., Foroozanfard, F., Jamilian, M., Akbari, H., Rahmani, E., Ahmadi, S., Taghizadeh, M., Memarzadeh, M. R., & Asemi, Z. (2017). The Effects of Omega-3 Fatty Acids and Vitamin E Co-Supplementation on Indices of Insulin Resistance and Hormonal Parameters in Patients with Polycystic Ovary Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial. Experimental and Clinical Endocrinology & Diabetes: Official Journal, German Society of Endocrinology [and] German Diabetes Association, 125(6), 353–359. https://pubmed.ncbi.nlm.nih.gov/28407657/ (B)
  9. Fang, F., Ni, K., Cai, Y., Shang, J., Zhang, X., & Xiong, C. (2017). Effect of vitamin D supplementation on polycystic ovary syndrome: A systematic review and meta-analysis of randomized controlled trials. Complementary Therapies in Clinical Practice, 26, 53–60. https://pubmed.ncbi.nlm.nih.gov/28107851/ (A)
  10. Fazelian, S., Rouhani, M. H., Bank, S. S., & Amani, R. (2017). Chromium supplementation and polycystic ovary syndrome: A systematic review and meta-analysis. Journal of Trace Elements in Medicine and Biology: Organ of the Society for Minerals and Trace Elements, 42, 92–96. https://pubmed.ncbi.nlm.nih.gov/28595797/ (A)
  11. Gilbert, E. W., Tay, C. T., Hiam, D. S., Teede, H. J., & Moran, L. J. (2018). Comorbidities and complications of polycystic ovary syndrome: An overview of systematic reviews. Clinical Endocrinology, 89(6), 683–699. https://pubmed.ncbi.nlm.nih.gov/30099747/ (A)
  12. Jamilian, M., & Asemi, Z. (2015). Chromium Supplementation and the Effects on Metabolic Status in Women with Polycystic Ovary Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial. Annals of Nutrition & Metabolism, 67(1), 42–48. https://pubmed.ncbi.nlm.nih.gov/26279073/ (B)
  13. Jamilian, M., Bahmani, F., Siavashani, M. A., Mazloomi, M., Asemi, Z., & Esmaillzadeh, A. (2016). The Effects of Chromium Supplementation on Endocrine Profiles, Biomarkers of Inflammation, and Oxidative Stress in Women with Polycystic Ovary Syndrome: a Randomized, Double-Blind, Placebo-Controlled Trial. Biological Trace Element Research, 172(1), 72–78. https://pubmed.ncbi.nlm.nih.gov/26613790/ (B)
  14. Jamilian, M., Foroozanfard, F., Rahmani, E., Talebi, M., Bahmani, F., & Asemi, Z. (2017). Effect of Two Different Doses of Vitamin D Supplementation on Metabolic Profiles of Insulin-Resistant Patients with Polycystic Ovary Syndrome. Nutrients, 9(12). https://pubmed.ncbi.nlm.nih.gov/29186759/ (B)
  15. Jamilian, M., Zadeh Modarres, S., Amiri Siavashani, M., Karimi, M., Mafi, A., Ostadmohammadi, V., & Asemi, Z. (2018). The Influences of Chromium Supplementation on Glycemic Control, Markers of Cardio-Metabolic Risk, and Oxidative Stress in Infertile Polycystic ovary Syndrome Women Candidate for In vitro Fertilization: a Randomized, Double-Blind, Placebo-Controlled Trial. Biological Trace Element Research, 185(1), 48–55. https://pubmed.ncbi.nlm.nih.gov/29307112/ (C)
  16. Łagowska, K., Bajerska, J., & Jamka, M. (2018). The Role of Vitamin D Oral Supplementation in Insulin Resistance in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Nutrients, 10(11). https://pubmed.ncbi.nlm.nih.gov/30400199/ (A)
  17. Li, M.-F., Zhou, X.-M., & Li, X.-L. (2018). The Effect of Berberine on Polycystic Ovary Syndrome Patients with Insulin Resistance (PCOS-IR): A Meta-Analysis and Systematic Review. Evidence-Based Complementary and Alternative Medicine: eCAM, 2018, 2532935. https://pubmed.ncbi.nlm.nih.gov/30538756/ (A)
  18. Nasri, K., Hantoushzadeh, S., Aghadavod, E., Taghizadeh, M., & Asemi, Z. (2017). The Effects of Omega-3 Fatty Acids Supplementation on Gene Expression Involved in the Insulin and Lipid Signaling Pathway in Patients with Polycystic Ovary Syndrome. Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones et Metabolisme, 49(6), 446–451. https://pubmed.ncbi.nlm.nih.gov/28235206/ (B)
  19. Nordio, M., Basciani, S., & Camajani, E. (2019). The 40:1 myo-inositol/D-chiro-inositol plasma ratio is able to restore ovulation in PCOS patients: comparison with other ratios. European Review for Medical and Pharmacological Sciences, 23(12), 5512–5521. https://pubmed.ncbi.nlm.nih.gov/31298405/ (C)
  20. Nordio, M., & Proietti, E. (2012). The combined therapy with myo-inositol and D-chiro-inositol reduces the risk of metabolic disease in PCOS overweight patients compared to myo-inositol supplementation alone. European Review for Medical and Pharmacological Sciences, 16(5), 575–581. https://pubmed.ncbi.nlm.nih.gov/22774396/ (C)
  21. Pizzo, A., Laganà, A. S., & Barbaro, L. (2014). Comparison between effects of myo-inositol and D-chiro-inositol on ovarian function and metabolic factors in women with PCOS. Gynecological Endocrinology: The Official Journal of the International Society of Gynecological Endocrinology, 30(3), 205–208. https://pubmed.ncbi.nlm.nih.gov/24351072/ (C)
  22. Rahmani, E., Samimi, M., Ebrahimi, F. A., Foroozanfard, F., Ahmadi, S., Rahimi, M., Jamilian, M., Aghadavod, E., Bahmani, F., Taghizadeh, M., Memarzadeh, M. R., & Asemi, Z. (2017). The effects of omega-3 fatty acids and vitamin E co-supplementation on gene expression of lipoprotein(a) and oxidized low-density lipoprotein, lipid profiles and biomarkers of oxidative stress in patients with polycystic ovary syndrome. Molecular and Cellular Endocrinology, 439, 247–255. https://pubmed.ncbi.nlm.nih.gov/27619403/ (B)
  23. Sadeghi, F., Alavi-Naeini, A., Mardanian, F., Ghazvini, M. R., & Mahaki, B. (2020). Omega-3 and vitamin E co-supplementation can improve antioxidant markers in obese/overweight women with polycystic ovary syndrome. International Journal for Vitamin and Nutrition Research. Internationale Zeitschrift Fur Vitamin- Und Ernahrungsforschung. Journal International de Vitaminologie et de Nutrition, 90(5-6), 477–483. https://pubmed.ncbi.nlm.nih.gov/30961460/ (C)
  24. Seyyed Abootorabi, M., Ayremlou, P., Behroozi-Lak, T., & Nourisaeidlou, S. (2018). The effect of vitamin D supplementation on insulin resistance, visceral fat and adiponectin in vitamin D deficient women with polycystic ovary syndrome: a randomized placebo-controlled trial. Gynecological Endocrinology: The Official Journal of the International Society of Gynecological Endocrinology, 34(6), 489–494. https://pubmed.ncbi.nlm.nih.gov/29271278/ (C) 
  25. Wei, W., Zhao, H., Wang, A., Sui, M., Liang, K., Deng, H., Ma, Y., Zhang, Y., Zhang, H., & Guan, Y. (2012). A clinical study on the short-term effect of berberine in comparison to metformin on the metabolic characteristics of women with polycystic ovary syndrome. European Journal of Endocrinology / European Federation of Endocrine Societies, 166(1), 99–105. https://pubmed.ncbi.nlm.nih.gov/22019891/ (C)
  26. Yang, K., Zeng, L., Bao, T., & Ge, J. (2018). Effectiveness of Omega-3 fatty acid for polycystic ovary syndrome: a systematic review and meta-analysis. Reproductive Biology and Endocrinology: RB&E, 16(1), 27. https://pubmed.ncbi.nlm.nih.gov/29580250/ (A) 
  27. Zeng, L., & Yang, K. (2018). Effectiveness of myoinositol for polycystic ovary syndrome: a systematic review and meta-analysis. Endocrine, 59(1), 30–38. https://pubmed.ncbi.nlm.nih.gov/29052180/ (A)

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